chr14-75980730-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_003239.5(TGFB3):c.164G>A(p.Ser55Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55T) has been classified as Uncertain significance.
Frequency
Consequence
NM_003239.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.164G>A | p.Ser55Asn | missense_variant | 1/7 | ENST00000238682.8 | |
TGFB3 | NM_001329939.2 | c.164G>A | p.Ser55Asn | missense_variant | 2/8 | ||
TGFB3 | NM_001329938.2 | c.164G>A | p.Ser55Asn | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB3 | ENST00000238682.8 | c.164G>A | p.Ser55Asn | missense_variant | 1/7 | 1 | NM_003239.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000933 AC: 142AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000338 AC: 85AN: 251492Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135922
GnomAD4 exome AF: 0.000114 AC: 166AN: 1461894Hom.: 1 Cov.: 31 AF XY: 0.000106 AC XY: 77AN XY: 727248
GnomAD4 genome AF: 0.000945 AC: 144AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61AN XY: 74468
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 24, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 18, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2022 | See Variant Classification Assertion Criteria. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2018 | Variant summary: TGFB3 c.164G>A (p.Ser55Asn) results in a conservative amino acid change located in the TGF-beta, propeptide domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 277224 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0042 in the gnomAD database. This frequency within African control individuals is approximately 168-fold above the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.164G>A has been reported in the literature in an individual affected with aortic root dilation, both parents carried the variant and were unaffected, supporting a benign role (Herrick_2017). Co-occurrence with a pathogenic variant has been observed by our lab (TTR c.424G>A, p.V142I), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Nov 28, 2018 | - - |
Rienhoff syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at